부산대학교 도서관

BACKGROUND AND PURPOSE:: Although inorganic arsenite (As) is toxic in humans, it has recently emerged as an effective chemotherapeutic agent for acute promyelocytic leukemia (APL). In humans and most animals, As is enzymatically methylated in the liver to weakly toxic dimethylarsinic acid (DMAs) that is a major pentavalent methylarsenic metabolite. Recent reports have indicated that trivalent methylarsenicals are produced through methylation of As and participate in arsenic poisoning. Trivalent methylarsenicals may be generated as arsenical–glutathione conjugates, such as dimethylarsinous glutathione (DMAsG), during the methylation process. However, less information is available on the cytotoxicity of DMAsG. EXPERIMENTAL APPROACH:: We synthesized and purified DMAsG using high performance TLC (HPTLC) methods and measured its cytotoxicity in rat liver cell line (TRL 1215 cells). KEY RESULTS:: DMAsG was highly cytotoxic in TRL 1215 cells with a LC50 of 160 nM. We also found that DMAsG molecule itself was not transported efficiently into the cells and was not cytotoxic; however it readily became strongly cytotoxic by dissociating into trivalent dimethylarsenicals and glutathione (GSH). The addition of GSH in micromolar physiological concentrations prevented the breakdown of DMAsG, and the DMAsG-induced cytotoxicity. Physiological concentrations of normal human serum (HS), human serum albumin (HSA), and human red blood cells (HRBC) also reduced both the cytotoxicity and cellular arsenic uptake induced by exposure to DMAsG. CONCLUSIONS AND IMPLICATIONS:: These findings suggest that the significant cytotoxicity induced by DMAsG may not be seen in healthy humans, even if DMAsG is formed in the body from As.